AN AUTOSOMAL GENOMIC SCAN FOR LOCI LINKED TO PREDIABETIC PHENOTYPES IN PIMA-INDIANS

Type 2 diabetes mellitus is a common chronic disease that is thought t o have a substantial genetic basis. Identification of the genes respon sible has been hampered by the complex nature of the syndrome. Abnorma lities in insulin secretion and insulin action predict the development of type 2 diabetes and are, themselves, highly heritable traits. Sinc e fewer genes may contribute to these precursors of type 2 diabetes th an to the overall syndrome, such genes may be easier to identify. We, therefore, undertook an autosomal genomic scan to identify loci linked to prediabetic traits in Pima Indians, a population with a high preva lence of type 2 diabetes. 363 nondiabetic Pima Indians were genotyped at 516 polymorphic microsatellite markers on all 22 autosomes, Linkage analyses were performed using three methods (single-marker, nonparame tric multipoint [MAPMAKER/SIBS], and variance components multipoint). These analyses provided evidence for linkage at several chromosomal re gions, including 3q21-24 linked to fasting plasma insulin concentratio n and in vivo insulin action, 4p15-q12 linked to fasting plasma insuli n concentration, 9q21 linked to 2-h insulin concentration during oral glucose tolerance testing, and 22q12-13 linked to fasting plasma gluco se concentration. These results suggest loci that may harbor genes con tributing to type 2 diabetes in Pima Indians. None of the linkages exc eeded a LOD score of 3.6 (a 5% probability of occurring in a genome-wi de scan). These findings must, therefore, be considered tentative unti l extended in this population or replicated in others.